Investigating the link between REV-ERB and HIF-1a in Th17 cell function

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SUMMARY Autoimmune diseases (i.e., rheumatoid arthritis (RA), Type I Diabetes mellitus (T1DM), multiple sclerosis (MS), Crohn's disease, etc.) affect at least 3% of the US population, although this number appears to be significantly increasing since 2020. Interestingly, many autoimmune diseases occur disproportionately in women. These diseases are chronic, debilitating, and often, life threatening. Recent advances in biologic therapeutics have been successful in reducing symptoms of these chronic diseases in many patients. However, due to the costs associated with these treatments, many Americans still go untreated. In fact, several recent reports have described health disparities in women of Hispanic, African American, and Native American descent, due to availability of healthcare and cost-effective therapies. There is a clear unmet need for lower cost therapeutics for autoimmune diseases. To develop new therapies for autoimmune diseases, we need to further our understanding of the physiological and cellular mechanisms controlling activation and differentiation of Th17 cells. Th17 cells are a subtype of CD4+ lymphocytes that produce the pro-inflammatory cytokine interleukin 17a (IL-17a). Dysregulated activity of Th17 cells is associated with several autoimmune diseases including multiple sclerosis, rheumatoid arthritis, psoriasis, and others. Many of the current biologic therapies target the interleukins produced by Th17 cells to reduce aberrant inflammatory processes. HIF-1 is a transcription factor that plays an important role in the metabolic regulation of Th17 cells. Interestingly, the nuclear receptor REV- ERB, regulates both the Th17 cell activation and differentiation by competing with RORt, and recent work by our lab indicates that REV-ERB may directly repress the expression of HIF-1, providing a “two-hit” mechanism to suppressing T-cell mediated autoimmune diseases. This proposal aims to investigate the role that REV-ERB plays in HIF-1 expression and determine the cellular changes that occur in T-cells during activation with and without the presence of REV-ERB ligands. The data obtained from this work will provide novel insights to the role that REV-ERB plays in T-cell physiology, and provide preliminary data for future drug discovery efforts.